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. 2016 Jun 9;7(8):797-801.
doi: 10.1021/acsmedchemlett.6b00194. eCollection 2016 Aug 11.

Aligning Potency and Pharmacokinetic Properties for Pyridine-Based NCINIs

Lee D Fader  1 , Murray Bailey  1 , Eric Beaulieu  1 , François Bilodeau  1 , Pierre Bonneau  1 , Yves Bousquet  1 , Rebekah J Carson  1 , Catherine Chabot  1 , René Coulombe  1 , Jianmin Duan  1 , Craig Fenwick  1 , Michel Garneau  1 , Ted Halmos  1 , Araz Jakalian  1 , Clint James  1 , Stephen H Kawai  1 , Serge Landry  1 , Steven R LaPlante  1 , Stephen W Mason  1 , Sebastien Morin  1 , Nathalie Rioux  1 , Bruno Simoneau  1 , Simon Surprenant  1 , Bounkham Thavonekham  1 , Carl Thibeault  1 , Thao Trinh  1 , Youla Tsantrizos  1 , Jennifer Tsoung  1 , Christiane Yoakim  1 , Dominik Wernic  1
Affiliations

Aligning Potency and Pharmacokinetic Properties for Pyridine-Based NCINIs

Lee D Fader et al. ACS Med Chem Lett. .

Abstract

Optimization of pyridine-based noncatalytic site integrase inhibitors (NCINIs) based on compound 2 has led to the discovery of molecules capable of inhibiting virus harboring N124 variants of HIV integrase (IN) while maintaining minimal contribution of enterohepatic recirculation to clearance in rat. Structure-activity relationships at the C6 position established chemical space where the extent of enterohepatic recirculation in the rat is minimized. Desymmetrization of the C4 substituent allowed for potency optimization against virus having the N124 variant of integrase. Combination of these lessons led to the discovery of compound 20, having balanced serum-shifted antiviral potency and minimized excretion in to the biliary tract in rat, potentially representing a clinically viable starting point for a new treatment option for individuals infected with HIV.

Keywords: HIV integrase; NCINI; enterohepatic recirculation.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Ratio of i.v. t1/2 (rat) and i.v. t1/2 (bile duct cannulated rat) as a function of %parent excreted as the acyl glucuronide into the biliary tract.
See this image and copyright information in PMC

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